NF1 is a common autosomal dominant disorder that affects approximately 1:3000 people worldwide (over 100,000 individuals in the United States alone) and predisposes to the development of both benign and malignant tumors, including optic glioma and malignant peripheral nerve sheath tumor (MPNST). Optic glioma (astrocytoma) represents the second most common tumor occurring in individuals with NF1. Optic gliomas affect at least 15% of children with NF1, typically in the first decade of life, with 52% of affected children developing signs or symptoms from their tumors. Optic pathway tumors can lead to blindness or invade into nearby brain regions or the subarachnoid space to result in precocious puberty or other neurological abnormalities.
The most commonly used therapy for optic pathway glioma in NF1 is chemotherapy, involving the combination of carboplatin and vincristine. Although initial clinical responses are observed in 60-80% of children with low-grade glioma, tumor progression occurs in 36% of children with optic pathway glioma, necessitating additional therapy. MPNSTs are highly aggressive and malignant tumors composed of neoplastic Schwann cells. Recent studies have shown that MPNSTs are not uncommon cancers in NF1, and affect nearly 10% of individuals with NF1. MPNSTs frequently recur after treatment, and often metastasize to lung and other organs. Current treatment is wide local excision followed by local radiation. However, 5-year survival rates are dismal, and no effective chemotherapy regimens are available. In addition, mean survival appears to be worse in NF1 subjects with MPNST than for those in the general population.
There is an unmet need in the art for more effective treatment of these tumors. New treatment discovery is heavily dependent on the ability to evaluate new chemotherapeutic compounds that target this important neurofibromin growth regulatory pathway.